Document Detail


Lipopolysaccharide-enhanced transcellular transport of HIV-1 across the blood-brain barrier is mediated by the p38 mitogen-activated protein kinase pathway.
MedLine Citation:
PMID:  18295207     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Chronic systemic inflammation in the late stage of human immunodeficiency virus type-1 (HIV-1) infection could increase neuroinvasion of infected monocytes and cell-free virus, causing an aggravation of neurological disorders in AIDS patients. We previously showed that the peripheral administration of lipopolysaccharide (LPS) enhanced the uptake across the blood-brain barrier (BBB) of the HIV-1 viral protein gp120. Brain microvessel endothelial cells are targets of LPS. Here, we investigated whether the direct interaction between LPS and the BBB also affected HIV-1 transport using primary mouse brain microvessel endothelial cells (BMECs). LPS produced a dose (1-100 microg/mL)- and time (0.5-4 h)-dependent increase in HIV-1 transport and a decrease in transendothelial electrical resistance (TEER). Whereas indomethacin (cyclooxygenase inhibitor) and L-NAME (NO synthase inhibitor) did not affect the LPS-induced changes in HIV-1 transport or TEER, pentoxifylline (TNF-alpha inhibitor) attenuated the decrease in TEER induced by LPS, but not the LPS-induced increase in HIV-1 transport. LPS also increased the phosphorylation of p44/42 MAPK and p38 MAPK but not that of JNK. U0126 (p44/42 MAPK inhibitor) and SP600125 (JNK inhibitor) did not inhibit the LPS-induced increase in HIV-1 transport although U0126 attenuated the reduction in TEER. SB203580 (p38 MAPK inhibitor) inhibited the LPS-induced increase in HIV-1 transport without affecting TEER. Thus, LPS-enhanced HIV-1 transport is independent of changes in TEER and so is attributed to increased transcellular trafficking of HIV-1 across the BBB. These results show that LPS increases HIV-1 transcellular transport across the BBB by a pathway that is mediated by p38 MAPK phosphorylation in BMECs.
Authors:
Shinya Dohgu; William A Banks
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2008-01-19
Journal Detail:
Title:  Experimental neurology     Volume:  210     ISSN:  0014-4886     ISO Abbreviation:  Exp. Neurol.     Publication Date:  2008 Apr 
Date Detail:
Created Date:  2008-04-04     Completed Date:  2008-06-20     Revised Date:  2014-09-20    
Medline Journal Info:
Nlm Unique ID:  0370712     Medline TA:  Exp Neurol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  740-9     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Analysis of Variance
Animals
Biological Transport / drug effects
Blood-Brain Barrier / drug effects,  physiology*
Cell Survival / drug effects
Cells, Cultured
Cerebral Cortex / cytology
Dose-Response Relationship, Drug
Drug Interactions
Endothelial Cells / drug effects,  physiology*
Enzyme Inhibitors / pharmacology
HIV-1 / metabolism*
Lipopolysaccharides / pharmacology
Mice
Mitogen-Activated Protein Kinases / physiology*
Phosphorylation / drug effects
Signal Transduction / drug effects,  physiology*
Grant Support
ID/Acronym/Agency:
N01-CO-12400/CO/NCI NIH HHS; R01 AG029839/AG/NIA NIH HHS; R01 NS050547/NS/NINDS NIH HHS; R01 NS050547-03/NS/NINDS NIH HHS; R01NS050547/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Lipopolysaccharides; EC 2.7.11.24/Mitogen-Activated Protein Kinases
Comments/Corrections

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